Possible drugs for enhanced chemoprophylaxis regimen
The mechanism of chemoprophylaxis is either killing of the causative organisms before the onset of pathology or killing of the pathogen allowing sub-clinical disease to heal or both. In leprosy, because the incubation period is very long, both mechanisms may be involved, though the latter may be more likely. The ideal enhanced regimen would reduce the risk of developing leprosy considerably more than 60% without inducing selection of drug-resistant mutants in leprosy, or other infectious diseases such as tuberculosis, which would lead to a higher risk of relapse and transmission of drug-resistant leprosy.
The Expert Meeting agreed that the PEP++ regimen should be comprised of drugs that are available in leprosy endemic countries and are approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Bedaquiline, oxazolidinone and nitro-dihydro-imidazo-oxazoles were excluded, because they have not been registered in the countries where the PEP++ research project is planned to take place (India, Brazil and Indonesia) or have not been used for the treatment of leprosy. The standard multidrug therapy (MDT) for leprosy, introduced in 1982, is a combination of dapsone and rifampicin for paucibacillary (PB) leprosy, and dapsone, rifampicin and clofazimine for multibacillary (MB) leprosy. MDT is associated with very low relapse rates in patients who complete treatment [
18]. Other drugs with known efficacy against leprosy are rifapentine, fluoroquinolones (such as ofloxacin, levofloxacin and moxifloxacin), minocycline and clarithromycin [
19].
In order to select the most potent drugs for the regimen, the Expert Meeting considered the bactericidal activity (ability to kill replicating bacteria), the sterilising activity (ability to kill non-replicating bacteria – persisters) as well as the bacteriostatic activity (ability to prevent bacterial growth) of the potential drugs. The effectiveness of the drugs discussed below has been evaluated on established infections in mouse footpads.
Rifampicin, routinely used for the treatment of leprosy, blocks the RNA-polymerase which is the first step of protein synthesis and prevents the replication of
M. leprae without killing on the spot actively-replicating bacteria. However, blocking the synthesis of proteins that are involved in the basic metabolism of non-replicating bacteria (persisters) prevents their survival, which means that rifampicin is actually a key sterilising drug. Shepard et al. [
20] demonstrated a complete loss of infectivity in mice of inocula from five lepromatous patients treated for 7 days with a daily dose of 600 mg of rifampicin. Rifampicin is well tolerated and when used as a single or repeated monthly dose very few side effects are seen, apart from discoloration of urine [
21].
Rifapentine is a rifamycin derivative like rifampicin, but has a longer plasma half-life of 14 to 18 h compared to rifampicin with only 3 h. The killing power of
M. leprae with a single dose rifapentine, determined by the proportional bactericidal technique in the mouse footpad model [
22], was 99.6% in contrast to the bactericidal activity of rifampicin which was 92.1% [
23]. Also,
M. leprae shows a lower minimum inhibitory concentration (MIC) for rifapentine than for rifampicin [
24]. Furthermore, fewer doses are needed to prevent relapse (12 weeks) in mouse models of tuberculosis, compared to 24 weeks for rifampicin, because the sterilising effect of rifapentine is stronger [
25]. However, the newly developed molecular viability assays indicate that the bactericidal effect of rifamycin derivates may be less rapid than the mouse footpad methods suggested [
26]. In conclusion, rifapentine would be a good choice as chemoprophylactic drug for leprosy because of its strong anti-mycobacterial potential. Nevertheless, experience with rifapentine in leprosy patients is limited and it is currently unavailable in most countries. It is accepted by the FDA for use in TB in the USA, but not by the EMA in Europe.
Even though the working mechanism of
clofazimine against
M. leprae is not fully understood, it appears to involve interference with the proton motive force and therefore bacterial adenosine triphosphate (ATP) production by membrane interaction with the respiratory chain and/or phospholipids [
27]. Clofazimine would be a potential candidate for the PEP++ regimen, because it is already used in MB MDT. Nevertheless, it has two big disadvantages: it lacks early bactericidal activity, taking weeks of daily use to build an effective tissue concentration, and it causes discoloration of the skin after about one month of treatment. Especially, the latter is a major concern for some people, because it is noticed by others and can take a long time to disappear. It is not known whether giving clofazimine intermittently is as effective as a daily dose, nor is it known whether intermittent use would completely prevent skin discoloration.
Dapsone is a bacteriostatic drug, used for leprosy treatment since 1945. It inhibits the bacterial nucleic acid synthesis, the building blocks of bacterial DNA. The infectiousness of
M. leprae, tested by inoculation of mice, reduces to 1% after 90 days of dapsone treatment [
28]. However, its extensive use as monotherapy for leprosy before the introduction of MDT, has contributed to the development of dapsone resistant leprosy strains.
In the group of fluoroquinolones,
moxifloxacin has the best bactericidal activity against
M. leprae in a murine model [
23]. It has a plasma half-life of around 12 h. The fluoroquinolones inhibit bacterial DNA synthesis by targeting the enzymatic activities of DNA gyrase, necessary for DNA replication. The bactericidal efficacy of moxifloxacin against
M. leprae in the mouse footpad model was 92.1% [
23]. Moxifloxacin is not routinely used as a drug for leprosy patients, but in a clinical proof-of-concept trial in eight multibacillary leprosy patients, moxifloxacin proved highly effective. In the trial patients, a single 400 mg dose of moxifloxacin resulted in significant killing (
P ≤ 0.006) of
M. leprae, ranging from 82 to 99%, with a mean of 91% [
29]. Skin lesions improved rapidly; subtle improvement in some patients was observed after a single 400 mg dose of moxifloxacin. In all eight patients definite improvement was observed with an additional week of daily moxifloxacin (day 14). Moxifloxacin is currently used for treatment of leprosy in a clinical trial in India (Kar, personal communication, November 2016).
Unlike some other fluoroquinolones, moxifloxacin demonstrated to have low propensity for causing phototoxic reactions in animal studies. But other findings in safety studies in animals (e.g. arthrotoxicity in juvenile animals and CNS toxicity) that have led to restrictions in the use of quinolones in general, have also been observed with moxifloxacin. Similar to other fluoroquinolones, moxifloxacin has been shown to cause lesions in the cartilage of the weight-bearing joints of immature animals. It should therefore not be used in children, or pregnant women unless the benefits outweigh the risks. Even though, there is lack of correlation between findings in juvenile animals and those in children [
30]. Preclinical studies, in which high doses of moxifloxacin were used, demonstrated the potential to induce convulsions. Caution is required with patients having an increased risk for tachyarrhythmia because it induces QT interval prolongation [
31]. However, a meta-analysis done to determine its effectiveness and safety for tuberculosis treatment concluded that the combination of moxifloxacin with the recommended regimen for the treatment of TB, with a daily dose of 400 mg given for at least 2 months, does not cause additional adverse events [
32].
The working mechanism of
ofloxacin is similar to that of moxifloxacin, but the bactericidal effect proved to be much less than moxifloxacin in the mouse footpad model (60.2% vs. 92.1%) and less adverse effects were observed [
23]. The plasma half-life of around 6 h is much shorter than that of moxifloxacin (around 12 h) and therefore the duration of the effect is also much shorter [
33,
34].
Minocycline is a semisynthetic tetracycline. Its bactericidal activity was shown in a trial where a single 200 mg dose of minocycline was given to eight lepromatous patients. This decreased the number of patients with viable
M. leprae, as demonstrated in mouse footpads (six of the eight patients) [
35]. However, the bactericidal effectiveness of minocycline against
M. leprae is less than that of rifampicin [
36]. As with other tetracyclines, it is contraindicated in children because it leads to discoloration of developing teeth, and may cause hypersensitivity (DRESS syndrome) in some patients [
37,
38]
.
The bactericidal effect of
clarithromycin for
M. leprae was 74.9% in the mouse footpad model [
23]. Clinical trials indicated that it is rapidly bactericidal for
M. leprae in humans [
39]. It is not routinely used in the treatment of leprosy, but it can safely be given to children. It was used as a prophylactic drug for leprosy in a trial in Indonesia conducted among healthy elementary school children in high-endemic areas in East Java province (Prakoeswa, personal communication, November 2016). An enhanced chemoprophylaxis regimen was given to children with high antibody titres (anti-PGL IgM) for leprosy: rifampicin 300 mg/day and clarithromycin 250 mg/day for the first ten days, followed by three months of intermittent two-weekly doses of rifampicin 300 mg and clarithromycin 250 mg. During the 5-year follow-up period the children were screened annually for signs/symptoms of leprosy and blood was taken to measure anti PGL-1 IgM titres. Although no control group was included in the study and a substantial proportion of the children was lost to follow-up, several important observations were made. Rifampicin and clarithromycin were well tolerated, no major adverse events were seen, none of the children was diagnosed with leprosy during the follow-up period, and 87% of the children had a decrease in the anti PGL-1 IgM titres.
Qualifications of an optimal enhanced chemoprophylaxis regimen
An enhanced chemoprophylaxis regimen should meet several criteria. It should be highly effective, much more than the current SDR regimen, safe without substantial side effects, acceptable to people who are not ill, available, affordable, feasible to administer on a large scale, and should not induce drug resistance in leprosy or TB bacteria. Safety, effectiveness and affordability are commonly used to select chemoprophylaxis regimens, drug resistance is to be avoided in all use of antibiotics, the other criteria are more specific for the use of chemoprophylaxis for leprosy [
40].
The first criterion is effectiveness. The new regimen should be sufficiently bactericidal to treat people harbouring higher numbers of M. leprae likely to be present in those with subclinical infection. Potentially, it should be capable of curing early MB leprosy. Given that the current SDR PEP regimen is 60% effective, the new regimen should be substantially more effective to be worthwhile, e.g. offering a protective effectiveness of 80 to 90%. For an increased preventive effect, a long-acting antibiotic and/or repeated administration is necessary. Repeating doses have a greater bactericidal effect than a single dose.
The second criterion is safety. The regimen will be given to healthy individuals as a preventive measure. People may be reluctant to take multiple drugs or multiple doses when they do not feel sick. It is therefore of greatest importance to avoid any adverse event to the extent possible. Contraindications for any of the drugs in the regimen should be checked carefully, before providing the regimen.
The third criterion is acceptability. The regimen should be easily acceptable for healthy contacts, because they are not motivated to take the drugs by being ill. The tablets or capsules should be easy to swallow and for smaller children the availability of the drug as a syrup would be preferred. Also, the schedule for the intake of the drugs should be simple enough to adhere to and the number of repeating doses should be limited. Furthermore, the regimen should ideally not induce any side effects, such as nausea, dizziness, headaches or skin discoloration.
The fourth criterion is availability of the drug. The drug should be available in the countries where the PEP++ research project is taking place at an affordable rate (fifth criterion).
The sixth criterion, feasibility to administer the regimen on a large scale is a combination of the above criteria, but also encompasses logistical aspects. It should be possible to widely distribute the drugs in adequate amounts. Storage requirements for the drugs should be simple and the shelf life sufficiently long.
The seventh criterion is that the prophylaxis should
not induce drug resistance in
M. leprae or
M. tuberculosis. The probability of emergence of resistance depends on the mycobacterial load, the potency of drugs (pharmacodynamics) and the number of drugs (less in combinations of ≥2 drugs). It is known that repeated doses of one drug will increase the risk of the development of resistance. To prevent this, a combination of drugs is preferred when giving multiple doses [
41]. Antimicrobial resistance is well known in leprosy. Rifampicin resistance was first described in 1976 and fluoroquinolones resistance in 1997 [
42,
43]
. The antimicrobial resistance proportion was estimated to be 8%, in a first prospective open survey conducted by a WHO surveillance network in the period 2009–2015 [
44].
Specific interventions to address concerns about resistance, such as surveillance, will be established during the PEP++ research project. Additional logistical considerations must be taken into account in the development of the final field protocol. These considerations are beyond the scope of this report and will be detailed in a future publication.
Possible drug combinations for enhanced chemoprophylaxis
Theoretically, one or two months of MDT treatment could be used as prophylactic treatment. Two months of MDT or one month of MDT ending with a monthly dose of rifampicin would appear to be a feasible regimen. The efficacy of MDT is known, it uses the same drugs for adults and children, it is available and it is accepted in all leprosy endemic counties. However, if standard MDT is given as preventive treatment, contacts and community members may perceive this as leprosy treatment and think that people taking this medication are leprosy patients. Moreover, on the basis of safety considerations, dapsone should not be included in the regimen since it occasionally causes a potentially fatal hypersensitivity syndrome [
45], while its bacteriostatic properties are unlikely to have an additional beneficial effect. Clofazimine is not preferred because of the late bactericidal activity and the discoloration of the skin it causes. This is not easily accepted by people, as it is associated with being on treatment for leprosy.
ROM has been used to treat single lesion leprosy. Compared to rifampicin, ofloxacin and minocycline have been shown to be less bactericidal in mouse models [
46,
47]. ROM is no more bactericidal than rifampicin alone [
46]. A combination of rifampicin with a more powerful bactericidal drug would therefore be preferred for optimal efficacy of a chemoprophylactic regimen.
Rifampicin remains a good candidate as component of the enhanced regimen, although its short half-life is a limitation. The wide use of single-dose rifampicin in the LPEP project has shown to be safe (no serious adverse events have been reported to date), acceptable, available and affordable [
17]. The Expert Meeting advised to combine rifampicin with moxifloxacin, the most bactericidal of the possible drugs for an enhanced regimen, with a longer half-life and good pharmacodynamic properties. It was agreed that the combination is likely to increase the protective effect of the chemoprophylaxis substantially, especially when repeated doses are given. Importantly, combining two antibiotics would reduce the likelihood of inducing resistance [
48]. Fluoroquinolones in general and moxifloxacin specifically have been used as chemoprophylaxis for TB, also in children; no serious adverse events were reported [
49‐
51]. However, fluoroquinolones are known to have potentially toxic side effects, especially in children, which need to be considered when they are used as prophylaxis instead of treatment of disease. The Expert Meeting therefore advised to replace moxifloxacin by clarithromycin when giving the chemoprophylaxis to children (< 16 years) and adults with a contraindication for moxifloxacin. Giving the combination of rifampicin and clarithromycin to all contacts, children as well as adults, is not preferred, because of the stronger bactericidal effect of moxifloxacin. Both rifampicin and clarithromycin can be given to children in syrup form.
To determine the frequency and duration of the use of the regimen, the Expert Meeting had the following considerations:
When rifampicin was introduced as component of MDT treatment, a monthly dose was recommended in view of the good therapeutic efficacy and the fact that this was better tolerated than a weekly dose and the lower costs compared to daily or weekly treatment [
52]. The Expert Meeting strongly advised that the enhanced regimen should also be given supervised to ensure compliance and repeatedly to increase the bactericidal effect. From a logistical point of view, a regimen that will be given daily for seven days is difficult to administer as an observed dose. An interval of one week or less is likely to cause more side effects [
53,
54]. A monthly dose is therefore preferred and more feasible as it is easier to be supervised. Giving three doses instead of one single dose was advised to increase the probability of killing more bacilli in an active metabolic state.
The contraindications used for SDR (pregnancy, liver or renal disorders, signs or symptoms of leprosy, signs or symptoms of TB, known allergy to rifampicin) would also apply to the enhanced regimen [
16]. In addition people with known cardiac or neurological disease, especially people suffering from seizures should be given clarithromycin instead of moxifloxacin.